Mature microRNAs (miRNAs) are naturally occurring, 22-nucleotide, noncoding RNAs that mediate posttranscriptional gene regulation. miRNAs play an important role in many biological processes, including differentiation and development, cell signaling, and response to infection, mostly by regulating genes involved in these processes. Overwhelming evidence indicates that dysregulation of miRNA expression is a cause or indicator of several disease processes, including many cancers. The discovery that circulating miRNAs are detectable in serum and plasma, and that their expression varies as a result of disease, presents great potential for circulating miRNA expression signatures to be used as biomarkers in disease diagnosis and prevention. There are currently hundreds of identified miRNAs for many model organisms. This set of known miRNAs for a given species (miRNome) is still small enough to easily screen the expression of all miRNAs in an experimental condition. However, enough characterization of miRNA expression changes in disease states or during pathway perturbations allows for the definition of smaller panels relevant to specific experimental model systems for analysis. Another approach is to focus simply on screening the best-characterized and highest-expressing miRNAs instead. Success of miRNA expression research relies on access to high-performance tools and technologies.